ABSTRACT
The DNA glycosylase MUTYH (mutY homolog (Escherichia coli)) counteracts the mutagenic effects of 8-oxo-7,8-dihydroguanine (8-oxodG) by removing adenine (A) misincorporated opposite the oxidized purine. Biallelic germline mutations in MUTYH cause the autosomal recessive MUTYH-associated adenomatous polyposis (MAP). Here we designed new tools to investigate the biochemical defects and biological consequences associated with different MUTYH mutations in human cells. To identify phenotype(s) associated with MUTYH mutations, lymphoblastoid cell lines (LCLs) were derived from seven MAP patients harboring missense as well as truncating mutations in MUTYH. These included homozygous p.Arg245His, p.Gly264TrpfsX7 or compound heterozygous variants (p.Gly396Asp/Arg245Cys, p.Gly396Asp/Tyr179Cys, p.Gly396Asp/Glu410GlyfsX43, p.Gly264TrpfsX7/Ala385ProfsX23 and p.Gly264TrpfsX7/Glu480del). DNA glycosylase assays of MAP LCL extracts confirmed that all these variants were defective in removing A from an 8-oxoG:A DNA substrate, but retained wild-type OGG1 activity. As a consequence of this defect, MAP LCLs accumulated DNA 8-oxodG in their genome and exhibited a fourfold increase in spontaneous mutagenesis at the PIG-A gene compared with LCLs from healthy donors. They were also hypermutable by KBrO3--a source of DNA 8-oxodG--indicating that the relatively modest spontaneous mutator phenotype associated with MUTYH loss can be significantly enhanced by conditions of oxidative stress. These observations identify accumulation of DNA 8-oxodG and a mutator phenotype as likely contributors to the pathogenesis of MUTYH variants.
Subject(s)
DNA Damage , DNA Glycosylases/genetics , DNA Glycosylases/metabolism , Genomic Instability , Oxidative Stress , 8-Hydroxy-2'-Deoxyguanosine , Adenomatous Polyposis Coli/genetics , Adenomatous Polyposis Coli/metabolism , Adult , Cell Line , DNA Repair , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/metabolism , Enzyme Activation , Female , Gene Expression , Heterozygote , Humans , Male , Membrane Proteins/genetics , Middle Aged , Mutation , Mutation Rate , PhenotypeABSTRACT
The term Communication generally designate the transmission of a message of concepts, feelings or needs from a speaker to a receiver by means of verbal or no verbal language. The pragmatic approach to human communication has put in evidence a further implication of this concept: every behaviour therefore has a value even when it is not intentional. Recently, a more dynamic concept of communication has been elaborated where communication means communicative action. This interpretation is the starting point for the theory of the "communicative acting" and subsequently of the so called discourse ethic elaborated by J. Habermas.
Subject(s)
Communication , Dictionaries as Topic , HumansABSTRACT
The term "human action" designates the intentional and deliberate movement that is proper and exclusive to mankind. Human action is a unified structure: knowledge, intention or volition, deliberation, decision or choice of means and execution. The integration between these dimensions appears as a task that demands strength of will to achieve the synthesis of self-possession and self-control that enables full personal realisation. Recently, the debate about the dynamism of human action has been enriched by the contribution of neurosciences. Thanks to techniques of neuroimaging, neurosciences have expanded the field of investigation to the nature of volition, to the role of the brain in decision-making processes and to the notion of freedom and responsibility.
Subject(s)
Decision Making , Human Activities , Problem Solving , Choice Behavior , Humans , Intention , Knowledge , Motivation , VolitionABSTRACT
A 32-year-old policeman injured his left wrist while engaged in judo training. A distal radio-ulnar dislocation, ulna dorsal, was reduced under general anesthesia, but, as the distal radio-ulnar joint was unstable, a Liebolt's ligamentous reconstruction procedure and a partial excision of the triangular fibrocartilage complex were carried out. The patient could resume his job eight weeks after the operation, and light training after a further six months. The need for proper physical examination and accurate radiographic positioning is stressed.
Subject(s)
Joint Dislocations/surgery , Martial Arts/injuries , Ulna/diagnostic imaging , Wrist Injuries/surgery , Adult , Humans , Joint Dislocations/diagnostic imaging , Male , Radiography , Wrist Injuries/diagnostic imagingABSTRACT
A case of bilateral congenital pseudarthrosis of the clavicle in a baby boy is described. The patient is fully asymptomatic, and no functional impairment is present. This is probably only the seventh case described of this rare congenital anomaly.
